With the advent of next generation sequencing, the frontier of challenges in genetics has shifted and is set to influence medical specialists beyond the clinical geneticist (Ware et al, 2012). Cardiologists certainly stand to benefit from the mass of information generated. Next generation sequencing, or massively parallel sequencing, refers to a rapid method of genetic sequencing that enables millions of DNA fragments to be decoded at the same time.

Understanding genetics has been likened to reading a book. First you have to work out the alphabet, this is the technical sequencing aspect of genetics. Then there comes putting it together in sentences and chapters, this is the analytical aspect, integrating bioinformatics data with the sequencing data. Next generation sequencing has made these 2 parts manageable and achievable in a meaningful timeline.

Finally however, we come to reading it all and making sense of the book. This interpretation, working out what the genetic code means is the next true bottleneck in genetics. Whilst it took 13 years for many different labs to work collaboratively to sequence the human genome, we can now do this in under a week.

There are few cardiac limited gene disorders with true Mendelian inheritance. With a few notable exceptions, such as familial hypercholesterolaemia, gene testing has not been very useful in clinical cardiology practice.

Next generation sequencing can include targeted sequencing for a particular gene or gene panel, whole exome sequencing (all the protein coding parts of the genome) or whole genome sequencing (all parts of the genome, including the coding exons and non coding introns) (Korf and Rehm, 2013).

In 2013, NHS England announced the 100K project, an ambitious 5 year strategy to perform whole genome sequencing in 100,000 patients. They will start with patients with cancer, rare diseases and infectious diseases. The aim is to link the DNA information to the patient’s medical records, to give doctors an understanding of the patient’s genetic status and how it might influence management. As the infrastructure and capabilities develop, this may extend beyond the initial remit of conditions.

In terms of what this means for cardiologists, the future explosion in genetic information means that associations will be discovered between genetic mutations and conditions, whether we had predicted these based on protein function or not. For example, in one of the early Whole Genome Sequencing projects running in the research setting, WGS 500 at the University of Oxford, novel genetic mutations were discovered in early onset epilepsy with an unexpected genetic mechanisms of disease (Martin et al, 2014).

Advancing further, we will need a detailed combination of genetics, bioinformatics, and detailed phenotyping to make sense of the information generated. This will necessitate a close relationship between research genetics, clinical geneticists and cardiologists.

Hypertrophic and dilated cardiomyopathies exemplify the benefits and difficulties in this field.

In the vast majority of cases of dilated cardiomyopathy, the underlying aetiology is not known. Approximately 50% of dilated cardiomyopathy is thought to be idiopathic, with an approximate equal split between sporadic and familial cases. There has now been a progressive discovery of the underlying but complex genetic aetiology (Hershberger et al, 2013). Genetic analysis now gives us the opportunity to re-organise our definition of the disease.

DCM is no longer thought to be one disease, but the end stage result of a variety of insults. Almost 30-40% of cases of idiopathic DCM are associated with mutations in over 30 genes. This reflects the diverse aetiology of dilated cardiomyopathy; these genes affect structures in the sarcomere, cytoskeleton, nuclear membrane, and mitochondria to name but a few. The diversity and prevalence of numerous low frequency gene mutations means the yield of genetic testing can be low, although in 2012, using next generation sequencing, the discovery of the presence of truncating mutations in the gene encoding titin, a sarcomeric protein, in up to 25% of patients with familial dilated cardiomyopathy and 18% of patients with sporadic idiopathic dilated cardiomyopathy, lead to a paradigm shift in our understanding of the aetiology of dilated cardiomyopathy (Herman et al, 2012). Currently however, in only a few situations does genetic testing in dilated cardiomyopathy change the management of patients, for example in the presence of the LMNA mutation (coding for lamin A/C, a nuclear membrane protein), dilated cardiomyopathy and conduction disease, an ICD is recommended in preference to a pacemaker, due to the high frequency of ventricular arrhythmias (Ackerman et al, 2011).

In hypertrophic cardiomyopathy, the genetic pool is a little smaller, with mutations in 5 genes (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) accounting for 90% of genetic causes. One of the leading indications for genetic testing is that the result should change the management of the patient (RCP Joint Report, 2011). However, only 30-60% of patients with hypertrophic cardiomyopathy have a known genetic mutation and genetic testing at present, does not lead to a significant change in management in the index case, although it does offer potential benefit to relatives.

Therefore future evolution of the use of genetic testing in cardiology is likely to involve consideration of cascade screening identifying the specific genetic abnormality in the relatives of the affected proband. The aim would be to identify early disease states to target these individuals for early surveillance and introduction of appropriate disease modifying therapy.

There is a small but emerging body of evidence for functional abnormalities in individuals with hypertrophic and dilated cardiomyopathy who are gene positive but seemingly unaffected and otherwise well (phenotype ‘negative’) (Ho et al, 2013; Lakdawala et al, 2012).

The cardiology community may look to the oncologists for guidance for how to manage the emergence of a cohort of cardiac gene positive phenotype negative individuals. Cancer predisposition genes, such as BRCA1 and BRCA2, have influenced the management of many women, not necessarily just those with a family history of breast or ovarian cancer. Appropriate interpretation of cancer predisposition genes can lead to improved diagnosis, optimised management, tailored treatment and improved cost efficacy in the management of patients, as well as help to address uncertainties and anxieties in relatives of affected patients (Rahman, 2014). It has taken many years to understand the complexity of these genetic abnormalities and the interpretation that must be made to understand pathogenicity of mutations in order to be able to appropriately advise women with these mutations. If cardiologists develop the skills to be able to integrate advanced genomics and detailed phenotyping, in the form of clinical assessment, surveillance, and advanced imaging modalities to gain the same level of understanding for emerging genetic mutations in cardiac conditions, then perhaps one day cardiology patients and their relatives may also benefit from the expanding genetic revolution.

Report of the Joint Committee on Medical Genetics (Royal College of Physicians, Royal College of Pathologists, British Society for Human Genetics). Consent and confidentiality in clinical genetic practice: Guidance on genetic testing and sharing genetic information. 2011. http://www.bsgm.org.uk/media/678746/consent_and_confidentiality_2011.pdf (accessed 23.2.14)